Niacin prodrugs and deuterated versions thereof

ABSTRACT

The invention relates to prodrugs of niacin and their use in pharmaceutical composition and therapeutic treatment of disease.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/262,292, filed on Nov. 18, 2009. The entire teachings of the aboveapplication are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Many current medicines suffer from poor absorption, distribution,metabolism and/or excretion (ADME) properties that prevent their wideruse. Poor ADME properties are also a major reason for the failure ofdrug candidates in clinical trials. While formulation technologies andprodrug strategies can be employed in some cases to improve certain ADMEproperties, these approaches often fail to address the underlying ADMEproblems that exist for many drugs and drug candidates. One such problemis rapid metabolism that causes a number of drugs, which otherwise wouldbe highly effective in treating a disease, to be cleared too rapidlyfrom the body. A possible solution to rapid drug clearance is frequentor high dosing to attain a sufficiently high plasma level of drug. This,however, introduces a number of potential treatment problems such aspoor patient compliance with the dosing regimen, side effects thatbecome more acute with higher doses, and increased cost of treatment.

In some select cases, a metabolic inhibitor will be co-administered witha drug that is cleared too rapidly. Such is the case with the proteaseinhibitor class of drugs that are used to treat HIV infection. The FDArecommends that these drugs be co-dosed with ritonavir, an inhibitor ofcytochrome P450 enzyme 3A4 (CYP3A4), the enzyme typically responsiblefor their metabolism (see Kempf, D. J. et al., Antimicrobial agents andchemotherapy, 1997, 41(3): 654-60). Ritonavir, however, causes adverseeffects and adds to the pill burden for HIV patients who must alreadytake a combination of different drugs. Similarly, the CYP2D6 inhibitorquinidine has been added to dextromethorphan for the purpose of reducingrapid CYP2D6 metabolism of dextromethorphan in a treatment ofpseudobulbar affect. Quinidine, however, has unwanted side effects thatgreatly limit its use in potential combination therapy (see Wang, L etal., Clinical Pharmacology and Therapeutics, 1994, 56(6 Pt 1): 659-67;and FDA label for quinidine at www.accessdata.fda.gov).

In general, combining drugs with cytochrome P450 inhibitors is not asatisfactory strategy for decreasing drug clearance. The inhibition of aCYP enzyme's activity can affect the metabolism and clearance of otherdrugs metabolized by that same enzyme. CYP inhibition can cause otherdrugs to accumulate in the body to toxic levels.

A potentially attractive strategy for improving a drug's metabolicproperties is deuterium modification. In this approach, one attempts toslow the CYP-mediated metabolism of a drug by replacing one or morehydrogen atoms with deuterium atoms. Deuterium is a safe, stable,non-radioactive isotope of hydrogen. Compared to hydrogen, deuteriumforms stronger bonds with carbon. In select cases, the increased bondstrength imparted by deuterium can positively impact the ADME propertiesof a drug, creating the potential for improved drug efficacy, safety,and/or tolerability. At the same time, because the size and shape ofdeuterium are essentially identical to those of hydrogen, replacement ofhydrogen by deuterium would not be expected to affect the biochemicalpotency and selectivity of the drug as compared to the original chemicalentity that contains only hydrogen.

Over the past 35 years, the effects of deuterium substitution on therate of metabolism have been reported for a very small percentage ofapproved drugs (see, e.g., Blake, Mich. et al, J Pharm Sci, 1975,64:367-91; Foster, A B, Adv Drug Res 1985, 14:1-40 (“Foster”); Kushner,D J et al, Can J Physiol Pharmacol 1999, 79-88; Fisher, M B et al, CurrOpin Drug Discov Devel, 2006, 9:101-09 (“Fisher”)). The results havebeen variable and unpredictable. For some compounds deuteration causeddecreased metabolic clearance in vivo. For others, there was no changein metabolism. Still others demonstrated increased metabolic clearance.The variability in deuterium effects has also led experts to question ordismiss deuterium modification as a viable drug design strategy forinhibiting adverse metabolism (see Foster at p. 35 and Fisher at p.101).

The effects of deuterium modification on a drug's metabolic propertiesare not predictable even when deuterium atoms are incorporated at knownsites of metabolism. Only by actually preparing and testing a deuterateddrug can one determine if and how the rate of metabolism will differfrom that of its non-deuterated counterpart. See, for example, Fukuto etal. (J. Med. Chem. 1991, 34, 2871-76). Many drugs have multiple siteswhere metabolism is possible. The site(s) where deuterium substitutionis required and the extent of deuteration necessary to see an effect onmetabolism, if any, will be different for each drug.

This invention relates to novel niacin prodrugs and pharmaceuticallyacceptable salts thereof. This invention also provides compositionscomprising a compound of this invention and the use of such compositionsin methods of treating diseases and conditions that are beneficiallytreated by administering niacin.

Niacin, also known as vitamin B3 or nicotinic acid, reduces serum levelsof total cholesterol, triglyceride, and low-density lipoprotein andincreases serum levels of high-density lipoproteins. One of the majorside effects of niacin administration is skin flushing.

Recently, laropiprant, known to minimize flushing due to niacinadministration, has been combined with niacin in an extended-releaseformulation (MK-524A). This combination has been approved in Europe forthe treatment of hypercholesterolemia and dyslipidemia under thetrademark Tredaptive®. However, approval of MK-524A in patients withheterozygous familial hypercholesterolemia had not been obtained. PhaseIII clinical trials of MK-524A for the treatment of atherosclerosis areongoing.

Despite the beneficial activities of niacin, there is a continuing needfor compositions or derivatives thereof that provide the beneficialeffects of niacin, but reduce or avoid the adverse side effects.

DEFINITIONS

The term “treat” means decrease, suppress, attenuate, diminish, arrest,or stabilize the development or progression of a disease (e.g., adisease or disorder delineated herein), lessen the severity of thedisease or improve the symptoms associated with the disease.

“Disease” means any condition or disorder that damages or interfereswith the normal function of a cell, tissue, or organ.

The term “alkyl” refers to a monovalent saturated hydrocarbon group.C₁-C₆ alkyl is an alkyl having from 1 to 6 carbon atoms. An alkyl may belinear or branched. Examples of alkyl groups include methyl; ethyl;propyl, including n-propyl and isopropyl; butyl, including n-butyl,isobutyl, sec-butyl, and t-butyl; pentyl, including, for example,n-pentyl, isopentyl, and neopentyl; and hexyl, including, for example,n-hexyl and 2-methylpentyl.

The term “cycloalkyl” refers to a monocyclic or bicyclic monovalentsaturated or non-aromatic unsaturated hydrocarbon ring system. The term“C₃-C₁₀ cycloalkyl” refers to a cycloalkyl wherein the number of ringcarbon atoms is from 3 to 10. Examples of C₃-C₁₀ cycloalkyl includeC₃-C₆ cycloalkyl. Bicyclic ring systems include fused, bridged, andspirocyclic ring systems. More particular examples of cycloalkyl groupsinclude, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cis- and trans-decalinyl, norbornyl, and spiro[4.5]decanyl.

The term “heterocycloalkyl” refers to a monocyclic or bicyclicmonovalent saturated or non-aromatic unsaturated ring system whereinfrom 1 to 4 ring atoms are heteroatoms independently selected from thegroup consisting of O, N and S. The term “3 to 10-memberedheterocycloalkyl” refers to a heterocycloalkyl wherein the number ofring atoms is from 3 to 10. Examples of 3 to 10-memberedheterocycloalkyl include 3 to 6-membered heterocycloalkyl. Bicyclic ringsystems include fused, bridged, and spirocyclic ring systems. Moreparticular examples of heterocycloalkyl groups include azepanyl,azetidinyl, aziridinyl, imidazolidinyl, morpholinyl, oxazolidinyl,oxazolidinyl, piperazinyl, piperidinyl, pyrazolidinyl, pyrrolidinyl,quinuclidinyl, and thiomorpholinyl.

The term “heteroaryl” refers to a monovalent aromatic monocyclic orbicyclic ring system wherein at least one ring atoms is a heteroatomindependently selected from the group consisting of O, N and S. The term5-membered heteroaryl refers to a heteroaryl wherein the number of ringatoms is 5. Examples of 5-membered heteroaryl groups include pyrrolyl,pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl,thiadiazolyl, furazanyl, imidazolinyl, and triazolyl. Bicyclicheteroaryl groups are typically 8, 9 or 10 membered. Examples includebenzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl,benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl,isoquinolinyl, indolyl, isoindolyl, or benzisoxazolyl.

It will be recognized that some variation of natural isotopic abundanceoccurs in a synthesized compound depending upon the origin of chemicalmaterials used in the synthesis. Thus, a preparation of niacin willinherently contain small amounts of deuterated isotopologues. Theconcentration of naturally abundant stable hydrogen and carbon isotopes,notwithstanding this variation, is small and immaterial as compared tothe degree of stable isotopic substitution of compounds of thisinvention. See, for instance, Wada, E et al., Seikagaku, 1994, 66:15;Gannes, L Z et al., Comp Biochem Physiol Mol Integr Physiol, 1998,119:725.

In the compounds of this invention any atom not specifically designatedas a particular isotope is meant to represent any stable isotope of thatatom. Unless otherwise stated, when a position is designatedspecifically as “H” or “hydrogen”, the position is understood to havehydrogen at its natural abundance isotopic composition. Also unlessotherwise stated, when a position is designated specifically as “D” or“deuterium”, the position is understood to have deuterium at anabundance that is at least 3340 times greater than the natural abundanceof deuterium, which is 0.015% (i.e., at least 50.1% incorporation ofdeuterium).

The term “isotopic enrichment factor” as used herein means the ratiobetween the isotopic abundance and the natural abundance of a specifiedisotope.

In other embodiments, a compound of this invention has an isotopicenrichment factor for each designated deuterium atom of at least 3500(52.5% deuterium incorporation at each designated deuterium atom), atleast 4000 (60% deuterium incorporation), at least 4500 (67.5% deuteriumincorporation), at least 5000 (75% deuterium), at least 5500 (82.5%deuterium incorporation), at least 6000 (90% deuterium incorporation),at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97%deuterium incorporation), at least 6600 (99% deuterium incorporation),or at least 6633.3 (99.5% deuterium incorporation).

The term “isotopologue” refers to a species that differs from a specificcompound of this invention only in the isotopic composition thereof.

The term “compound,” when referring to a compound of this invention,refers to a collection of molecules having an identical chemicalstructure, except that there may be isotopic variation among theconstituent atoms of the molecules. Thus, it will be clear to those ofskill in the art that a compound represented by a particular chemicalstructure containing indicated deuterium atoms, will also contain lesseramounts of isotopologues having hydrogen atoms at one or more of thedesignated deuterium positions in that structure. The relative amount ofsuch isotopologues in a compound of this invention will depend upon anumber of factors including the isotopic purity of deuterated reagentsused to make the compound and the efficiency of incorporation ofdeuterium in the various synthesis steps used to prepare the compound.However, as set forth above the relative amount of such isotopologues intoto will be less than 49.9% of the compound. In other embodiments, therelative amount of such isotopologues in toto will be less than 47.5%,less than 40%, less than 32.5%, less than 25%, less than 17.5%, lessthan 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% ofthe compound.

The invention also provides salts of the compounds of the invention.

A salt of a compound of this invention is formed between an acid and abasic group of the compound, such as an amino functional group, or abase and an acidic group of the compound, such as a carboxyl functionalgroup. According to another embodiment, the compound is apharmaceutically acceptable acid addition salt.

The term “pharmaceutically acceptable,” as used herein, refers to acomponent that is, within the scope of sound medical judgment, suitablefor use in contact with the tissues of humans and other mammals withoutundue toxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio. A “pharmaceuticallyacceptable salt” means any non-toxic salt that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention. A “pharmaceutically acceptable counterion”is an ionic portion of a salt that is not toxic when released from thesalt upon administration to a recipient.

Acids commonly employed to form pharmaceutically acceptable saltsinclude inorganic acids such as hydrogen bisulfide, hydrochloric acid,hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, aswell as organic acids such as para-toluenesulfonic acid, salicylic acid,tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylicacid, fumaric acid, gluconic acid, glucuronic acid, formic acid,glutamic acid, methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonicacid, carbonic acid, succinic acid, citric acid, benzoic acid and aceticacid, as well as related inorganic and organic acids. Suchpharmaceutically acceptable salts thus include sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide;iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate,succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate,terephthalate, sulfonate, xylene sulfonate, phenylacetate,phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate,glycolate, maleate, tartrate, methanesulfonate, propanesulfonate,naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and othersalts. In one embodiment, pharmaceutically acceptable acid additionsalts include those formed with mineral acids such as hydrochloric acidand hydrobromic acid, and especially those formed with organic acidssuch as maleic acid.

The compounds of the present invention (e.g., compounds of Formula I),may contain an asymmetric carbon atom, for example, as the result ofdeuterium substitution or otherwise. As such, compounds of thisinvention can exist as either individual enantiomers, or mixtures of thetwo enantiomers. Accordingly, a compound of the present invention mayexist as either a racemic mixture or a scalemic mixture, or asindividual respective stereoisomers that are substantially free fromanother possible stereoisomer. The term “substantially free of otherstereoisomers” as used herein means less than 25% of otherstereoisomers, preferably less than 10% of other stereoisomers, morepreferably less than 5% of other stereoisomers and most preferably lessthan 2% of other stereoisomers are present. Methods of obtaining orsynthesizing an individual enantiomer for a given compound are known inthe art and may be applied as practicable to final compounds or tostarting material or intermediates.

Unless otherwise indicated, when a disclosed compound is named ordepicted by a structure without specifying the stereochemistry and hasone or more chiral centers, it is understood to represent all possiblestereoisomers of the compound.

The term “stable compounds,” as used herein, refers to compounds whichpossess stability sufficient to allow for their manufacture and whichmaintain the integrity of the compound for a sufficient period of timeto be useful for the purposes detailed herein (e.g., formulation intotherapeutic products, intermediates for use in production of therapeuticcompounds, isolatable or storable intermediate compounds, treating adisease or condition responsive to therapeutic agents).

“D” and “d” both refer to deuterium. “Stereoisomer” refers to bothenantiomers and diastereomers. “Tert” and “t-” each refer to tertiary.“US” refers to the United States of America.

The term “substituted with deuterium” means that one or more hydrogenatoms in the indicated moiety are substituted with a deuterium atom.

Therapeutic Compounds

The present invention provides a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from C₁-C₆ alkyl, phenyl, a 5-10-membered heteroaryl, anda 3-10-membered heterocycloalkyl, wherein R¹ is optionally substitutedwith one or more substituents independently selected from halo anddeuterium; and

-   -   n is 0 or an integer from 1 to 4.

In certain embodiments, n is 0. In certain other embodiments, n is 1. Incertain other embodiments, n is 4.

In certain embodiments, R¹ is C₁-C₆ alkyl optionally substituted withone or more substituents independently selected from halo and deuterium.In one aspect of these embodiments, n is 0. In one aspect of theseembodiments, R¹ is C₁-C₆ alkyl substituted with one or more deuteriumatoms. As an example, R¹ is C₁-C₄ alkyl substituted with one or moredeuterium atoms.

In certain embodiments, R¹ comprises at least one deuterium atom. In oneaspect of these embodiments, n is 0. In one aspect of these embodiments,is —CD₃.

In certain embodiments, R¹ comprises at least one fluoride atom. In oneaspect of these embodiments, n is 0. In one aspect of these embodiments,R¹ is —CF₃.

In certain embodiments, R¹ is selected from —CH₃, —CD₃ and CF₃. In oneaspect of these embodiments, n is 0 or 4.

In yet another embodiment, the group

in Formula I is selected from

For example, the group

may be selected from

In yet another embodiment, the compound is selected from any one of

or a pharmaceutically acceptable salt of any of the foregoing.

In another set of embodiments, any atom not designated as deuterium inany of the embodiments set forth above is present at its naturalisotopic abundance.

In another embodiment, the compound is compound 103, or apharmaceutically acceptable salt therein, wherein any atom notdesignated as deuterium is present at its natural isotopic abundance,and wherein the percentage of deuterium incorporation at each positiondesignated as deuterium is at least 95%, more particularly at least 97%,even more particularly at least 99%, yet more particularly at least99.5%.

The synthesis of compounds of Formula I may be readily achieved bysynthetic chemists of ordinary skill by reference to the ExemplarySynthesis and Examples disclosed herein.

Exemplary Synthesis

Scheme 1 illustrates an exemplary preparation of a compound of FormulaI. As shown in Scheme 1, optionally deuterated niacin 1 is treated withR¹—SO₂NH₂ 2a, 2b or 2c in a manner analogous to the one described byAsaki, T. et al., Biorg. Med. Chem. 2007, 15, p. 7720 to provide acompound of Formula I wherein R¹ is CH₃, CD₃ or CF₃, respectively.

2a and 2c are commercially available. As shown in Scheme 2 below, 2b maybe prepared from commercially available 3 according to the proceduredescribed by Uno et al., Spectrochim. Acta 1975, 31A, 1217-25.

As an example, 1 in Scheme 1 may be niacin (1a) or commerciallyavailable deuterated niacin 1b, 1c or 1d:

As another example, 1 may be deuterated niacin 1e or 1f:

1e and 1f are each prepared as described by Clark, B. R., J. LabeledCompounds Radiopharm. 1976, 12, 535-40. 1e is prepared by reducingcommercially available 4 with D₂ as shown in Scheme 3a below, while 1fis prepared by treating 1a with palladium acetate andpoly(N-vinylpyrrolidine) followed by quenching with D₂O as shown inScheme 3b.

The specific approaches and compounds shown above are not intended to belimiting. The chemical structures in the schemes herein depict variablesthat are hereby defined commensurately with chemical group definitions(moieties, atoms, etc.) of the corresponding position in the compoundformulae herein, whether identified by the same variable name (i.e., R¹,R², R³, etc.) or not. The suitability of a chemical group in a compoundstructure for use in the synthesis of another compound is within theknowledge of one of ordinary skill in the art.

Additional methods of synthesizing compounds of Formula I and theirsynthetic precursors, including those within routes not explicitly shownin schemes herein, are within the means of chemists of ordinary skill inthe art. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing theapplicable compounds are known in the art and include, for example,those described in Larock R, Comprehensive Organic Transformations, VCHPublishers (1989); Greene, T W et al., Protective Groups in OrganicSynthesis, 3^(rd) Ed., John Wiley and Sons (1999); Fieser, L et al.,Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons(1994); and Paquette, L, ed., Encyclopedia of Reagents for OrganicSynthesis, John Wiley and Sons (1995) and subsequent editions thereof.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds.

Compositions

The invention also provides pyrogen-free pharmaceutical compositionscomprising an effective amount of a compound of Formula I (e.g.,including any of the formulae herein), or a pharmaceutically acceptablesalt of said compound; and a pharmaceutically acceptable carrier. Thecarrier(s) are “acceptable” in the sense of being compatible with theother ingredients of the formulation and, in the case of apharmaceutically acceptable carrier, not deleterious to the recipientthereof in an amount used in the medicament.

Pharmaceutically acceptable carriers, adjuvants and vehicles that may beused in the pharmaceutical compositions of this invention include, butare not limited to, ion exchangers, alumina, aluminum stearate,lecithin, scrum proteins, such as human serum albumin, buffer substancessuch as phosphates, glycine, sorbic acid, potassium sorbate, partialglyceride mixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

If required, the solubility and bioavailability of the compounds of thepresent invention in pharmaceutical compositions may be enhanced bymethods well-known in the art. One method includes the use of lipidexcipients in the formulation. See “Oral Lipid-Based Formulations:Enhancing the Bioavailability of Poorly Water-Soluble Drugs (Drugs andthe Pharmaceutical Sciences),” David J. Hauss, ed. Informa Healthcare,2007; and “Role of Lipid Excipients in Modifying Oral and ParenteralDrug Delivery: Basic Principles and Biological Examples,” Kishor M.Wasan, ed. Wiley-Interscience, 2006.

Another known method of enhancing bioavailability is the use of anamorphous form of a compound of this invention optionally formulatedwith a poloxamer, such as LUTROL™ and PLURONIC™ (BASF Corporation), orblock copolymers of ethylene oxide and propylene oxide. See U.S. Pat.No. 7,014,866; and United States patent publications 20060094744 and20060079502.

The pharmaceutical compositions of the invention include those suitablefor oral, rectal, nasal, topical (including buccal and sublingual),vaginal or parenteral (including subcutaneous, intramuscular,intravenous and intradermal) administration. In certain embodiments, thecompound of the formulae herein is administered transdermally (e.g.,using a transdermal patch or iontophoretic techniques). Otherformulations may conveniently be presented in unit dosage form, e.g.,tablets, sustained release capsules, and in liposomes, and may beprepared by any methods well known in the art of pharmacy. See, forexample, Remington: The Science and Practice of Pharmacy, Lippincott.Williams & Wilkins, Baltimore, Md. (20th ed. 2000).

Such preparative methods include the step of bringing into associationwith the molecule to be administered ingredients such as the carrierthat constitutes one or more accessory ingredients. In general, thecompositions are prepared by uniformly and intimately bringing intoassociation the active ingredients with liquid carriers, liposomes orfinely divided solid carriers, or both, and then, if necessary, shapingthe product.

In certain embodiments, the compound is administered orally.Compositions of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, sachets, or tabletseach containing a predetermined amount of the active ingredient; apowder or granules; a solution or a suspension in an aqueous liquid or anon-aqueous liquid; an oil-in-water liquid emulsion; a water-in-oilliquid emulsion; packed in liposomes; or as a bolus, etc. Soft gelatincapsules can be useful for containing such suspensions, which maybeneficially increase the rate of compound absorption.

In the case of tablets for oral use, carriers that are commonly usedinclude lactose and corn starch. Lubricating agents, such as magnesiumstearate, are also typically added. For oral administration in a capsuleform, useful diluents include lactose and dried cornstarch. When aqueoussuspensions are administered orally, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweeteningand/or flavoring and/or coloring agents may be added.

Compositions suitable for oral administration include lozengescomprising the ingredients in a flavored basis, usually sucrose andacacia or tragacanth; and pastilles comprising the active ingredient inan inert basis such as gelatin and glycerin, or sucrose and acacia.

Compositions suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents. The formulations may be presented in unit-dose or multi-dosecontainers, for example, sealed ampules and vials, and may be stored ina freeze dried (lyophilized) condition requiring only the addition ofthe sterile liquid carrier, for example water for injections,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tablets.

Such injection solutions may be in the form, for example, of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to techniques known in the art using suitabledispersing or wetting agents (such as, for example, Tween 80) andsuspending agents. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are mannitol, water, Ringer's solution and isotonic sodiumchloride solution. In addition, sterile, fixed oils are conventionallyemployed as a solvent or suspending medium. For this purpose, any blandfixed oil may be employed including synthetic mono- or diglycerides.Fatty acids, such as oleic acid and its glyceride derivatives are usefulin the preparation of injectables, as are naturalpharmaceutically-acceptable oils, such as olive oil or castor oil,especially in their polyoxyethylated versions. These oil solutions orsuspensions may also contain a long-chain alcohol diluent or dispersant.

The pharmaceutical compositions of this invention may be administered inthe form of suppositories for rectal administration. These compositionscan be prepared by mixing a compound of this invention with a suitablenon-irritating excipient which is solid at room temperature but liquidat the rectal temperature and therefore will melt in the rectum torelease the active components. Such materials include, but are notlimited to, cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention may be administered bynasal aerosol or inhalation. Such compositions are prepared according totechniques well-known in the art of pharmaceutical formulation and maybe prepared as solutions in saline, employing benzyl alcohol or othersuitable preservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other solubilizing or dispersing agents known inthe art. See, e.g.: Rabinowitz J D and Zaffaroni A C, U.S. Pat. No.6,803,031, assigned to Alexza Molecular Delivery Corporation.

Topical administration of the pharmaceutical compositions of thisinvention is especially useful when the desired treatment involves areasor organs readily accessible by topical application. For topicalapplication topically to the skin, the pharmaceutical composition shouldbe formulated with a suitable ointment containing the active componentssuspended or dissolved in a carrier. Carriers for topical administrationof the compounds of this invention include, but are not limited to,mineral oil, liquid petroleum, white petroleum, propylene glycol,polyoxyethylene polyoxypropylene compound, emulsifying wax, and water.Alternatively, the pharmaceutical composition can be formulated with asuitable lotion or cream containing the active compound suspended ordissolved in a carrier. Suitable carriers include, but are not limitedto, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esterswax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. Thepharmaceutical compositions of this invention may also be topicallyapplied to the lower intestinal tract by rectal suppository formulationor in a suitable enema formulation. Topically-transdermal patches andiontophoretic administration are also included in this invention.

Application of the subject therapeutics may be local, so as to beadministered at the site of interest. Various techniques can be used forproviding the subject compositions at the site of interest, such asinjection, use of catheters, trocars, projectiles, pluronic gel, stents,sustained drug release polymers or other device which provides forinternal access.

Thus, according to yet another embodiment, the compounds of thisinvention may be incorporated into compositions for coating animplantable medical device, such as prostheses, artificial valves,vascular grafts, stents, or catheters. Suitable coatings and the generalpreparation of coated implantable devices are known in the art and areexemplified in U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. Thecoatings are typically biocompatible polymeric materials such as ahydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethyleneglycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof.The coatings may optionally be further covered by a suitable topcoat offluorosilicone, polysaccharides, polyethylene glycol, phospholipids orcombinations thereof to impart controlled release characteristics in thecomposition. Coatings for invasive devices are to be included within thedefinition of pharmaceutically acceptable carrier, adjuvant or vehicle,as those terms are used herein.

According to another embodiment, the invention provides a method ofcoating an implantable medical device comprising the step of contactingsaid device with the coating composition described above. It will beobvious to those skilled in the art that the coating of the device willoccur prior to implantation into a mammal.

According to another embodiment, the invention provides a method ofimpregnating an implantable drug release device comprising the step ofcontacting said drug release device with a compound or composition ofthis invention. Implantable drug release devices include, but are notlimited to, biodegradable polymer capsules or bullets, non-degradable,diffusible polymer capsules and biodegradable polymer wafers.

According to another embodiment, the invention provides an implantablemedical device coated with a compound or a composition comprising acompound of this invention, such that said compound is therapeuticallyactive.

According to another embodiment, the invention provides an implantabledrug release device impregnated with or containing a compound or acomposition comprising a compound of this invention, such that saidcompound is released from said device and is therapeutically active.

Where an organ or tissue is accessible because of removal from thesubject, such organ or tissue may be bathed in a medium containing acomposition of this invention, a composition of this invention may bepainted onto the organ, or a composition of this invention may beapplied in any other convenient way.

In another embodiment, a composition of this invention further comprisesa second therapeutic agent. The second therapeutic agent may be selectedfrom any compound or therapeutic agent known to have or thatdemonstrates advantageous properties when administered with a compoundhaving the same mechanism of action as niacin. Such agents include thoseindicated as being useful in combination with niacin, including but notlimited to, other cholesterol lowering agents (e.g., statins, fibrates,ezetimibe, HMG-CoA reductase inhibitors, a bile acid-binding resin),anti-diabetic drugs (e.g., PPAR-gamma activators), anti-platelet agents,pain-reducing agents; prostaglandin-D2 antagonists; and prostaglandin-D2receptor antagonists.

Preferably, the second therapeutic agent is an agent useful in thetreatment or prevention of a disease or condition selected from pain,coronary artery disease, type 2 diabetes, metabolic syndrome,atherosclerosis, hypercholesterolemia, blood vessel occlusions, anddyslipidemia.

In one embodiment, the second therapeutic agent is selected fromlovastatin, simvastatin, rosuvastatin, atorvastatin, ezetimibe, aspirin,laropiprant, colestipol, cholestyramine, fenofibrate, rosiglitazone,pioglitazone, clopidogrel, prednisone, oxycodone, prednisone and applepectin, and combinations of any of the foregoing.

In another embodiment, the second therapeutic agent is selected fromlovastatin, simvastatin and a combination of simvastatin and ezetimibe.

In one embodiment, the composition does not comprise a prostaglandin-D2antagonist or a prostaglandin-D2 receptor (DP₁) antagonist.

In another embodiment, the invention provides separate dosage forms of acompound of this invention and one or more of any of the above-describedsecond therapeutic agents, wherein the compound and second therapeuticagent are associated with one another. The term “associated with oneanother” as used herein means that the separate dosage forms arepackaged together or otherwise attached to one another such that it isreadily apparent that the separate dosage forms are intended to be soldand administered together (within less than 24 hours of one another,consecutively or simultaneously).

In the pharmaceutical compositions of the invention, the compound of thepresent invention is present in an effective amount. As used herein, theterm “effective amount” refers to an amount which, when administered ina proper dosing regimen, is sufficient to treat the target disorder.

The interrelationship of dosages for animals and humans (based onmilligrams per meter squared of body surface) is described in Freireichet al., Cancer Chemother. Rep, 1966, 50: 219. Body surface area may beapproximately determined from height and weight of the subject. See,e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 1970,537.

In one embodiment, an effective amount of a compound of this inventioncan range from 50 mg to 2,000 mg/dose with a dosing of one to threetimes per day.

Effective doses will also vary, as recognized by those skilled in theart, depending on the diseases, treated, the severity of the disease,the route of administration, the sex, age and general health conditionof the subject, excipient usage, the possibility of co-usage with othertherapeutic treatments such as use of other agents and the judgment ofthe treating physician. For example, guidance for selecting an effectivedose can be determined by reference to the prescribing information forniacin.

For pharmaceutical compositions that comprise a second therapeuticagent, an effective amount of the second therapeutic agent is betweenabout 20% and 100% of the dosage normally utilized in a monotherapyregime using just that agent. Preferably, an effective amount is betweenabout 70% and 100% of the normal monotherapeutic dose. The normalmonotherapeutic dosages of these second therapeutic agents are wellknown in the art. See, e.g., Wells et al., eds., PharmacotherapyHandbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDRPharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition,Tarascon Publishing, Loma Linda, Calif. (2000), each of which referencesare incorporated herein by reference in their entirety.

It is expected that some of the second therapeutic agents referencedabove will act synergistically with the compounds of this invention.When this occurs, it will allow the effective dosage of the secondtherapeutic agent and/or the compound of this invention to be reducedfrom that required in a monotherapy. This has the advantage ofminimizing toxic side effects of either the second therapeutic agent ofa compound of this invention, synergistic improvements in efficacy,improved ease of administration or use and/or reduced overall expense ofcompound preparation or formulation.

Methods of Treatment

In one embodiment, the invention provides a method of reducing flushingand/or nausea associated with the administration of niacin to a subjectcomprising the step of administering to the subject an effective amountof a compound of Structural Formula I, or a pharmaceutically acceptablesalt thereof in place of the niacin in the treatment. In one aspect ofthis embodiment, the compound of Structural Formula I, or apharmaceutically acceptable salt thereof is not co-administered with aprostaglandin-D2 antagonist or a prostaglandin-D2 receptor (DP₁)antagonist.

According to another embodiment, the invention provides a method oftreating a disease that is beneficially treated by niacin in a subjectin need thereof, comprising the step of administering to the subject aneffective amount of a compound of Structural Formula I, apharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable composition of this invention. Such diseases are well knownin the art and include, but are not limited to, niacin deficiency,elevated cholesterol or triglyceride levels (e.g hypercholesterolemia,dyslipidemia), reduced HDL levels, lipoprotein disorders,atherosclerosis, myocardial infarction, ischemic stroke, coronary arterydisease, retinal vein occlusions, reduced blood flow and/or reducedendothelial cell function in sickle cell disease, type 2 diabetes,metabolic syndrome, diabetic, nephropathy, and pain.

In one particular embodiment, the method of this invention is used totreat a disease or condition selected from hypercholesterolemia,dyslipidemia, ischemic stroke, lipoprotein disorders, atherosclerosis,myocardial infarction, and diabetic nephropathy in a subject in needthereof.

Identifying a subject in need of such treatment can be in the judgmentof a subject or a health care professional and can be subjective (e.g.opinion) or objective (e.g. measurable by a test or diagnostic method).

In another embodiment, any of the above methods of treatment comprisesthe further step of co-administering to the subject in need thereof oneor more second therapeutic agents. The choice of second therapeuticagent may be made from any second therapeutic agent known to be usefulfor co-administration with niacin. The choice of second therapeuticagent is also dependent upon the particular disease or condition to betreated. Examples of second therapeutic agents that may be employed inthe methods of this invention are those set forth above for use incombination compositions comprising a compound of this invention and asecond therapeutic agent.

In one embodiment, the invention provides a method of reducing elevatedtotal cholesterol or LDL-cholesterol by co-administering to a subject inneed thereof a composition of the present invention and a bileacid-binding resin.

In another embodiment, the invention provides a method of reducingelevated serum triglycerides, reducing the risk of recurrent nonfatalmyocardial infarction and/or promoting the regression or slowing theprogression of atherosclerosis by co-administering to a subject in needthereof a composition of the present invention and, a bile acid-bindingresin.

In yet another embodiment, the invention provides a method of increasinghigh-density lipoprotein cholesterol (HDL-C) and/or decreasing totaland/or low-density lipoprotein cholesterol (LDL-C), ApoB andtriglyceride levels by co-administering to a subject in need thereof acomposition of the present invention and a statin.

In still another embodiment, the invention provides a method of treatinga lipoprotein disorder by co-administering to a subject in need thereofa composition of the present invention and a second therapeutic agentselected from lovastatin and simvastatin.

In another set of embodiments, in any of the methods of treatment setforth above, the subject is not co-administered a prostaglandin-D2antagonist or a prostaglandin-D2 receptor (DP₁) antagonist.

The term “co-administered” as used herein means that the secondtherapeutic agent may be administered together with a compound of thisinvention as part of a single dosage form (such as a composition of thisinvention comprising a compound of the invention and an secondtherapeutic agent as described above) or as separate, multiple dosageforms. Alternatively, the additional agent may be administered prior to,consecutively with, or following the administration of a compound ofthis invention. In such combination therapy treatment, both thecompounds of this invention and the second therapeutic agent(s) areadministered by conventional methods. The administration of acomposition of this invention, comprising both a compound of theinvention and a second therapeutic agent, to a subject does not precludethe separate administration of that same therapeutic agent, any othersecond therapeutic agent or any compound of this invention to saidsubject at another time during a course of treatment.

Effective amounts of these second therapeutic agents are well known tothose skilled in the art and guidance for dosing may be found in patentsand published patent applications referenced herein, as well as in Wellset al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange,Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000),and other medical texts. However, it is well within the skilledartisan's purview to determine the second therapeutic agent's optimaleffective-amount range.

In one embodiment of the invention, where a second therapeutic agent isadministered to a subject, the effective amount of the compound of thisinvention is less than its effective amount would be where the secondtherapeutic agent is not administered. In another embodiment, theeffective amount of the second therapeutic agent is less than itseffective amount would be where the compound of this invention is notadministered. In this way, undesired side effects associated with highdoses of either agent may be minimized. Other potential advantages(including without limitation improved dosing regimens and/or reduceddrug cost) will be apparent to those of skill in the art.

In yet another aspect, the invention provides the use of a compound ofFormula I alone or together with one or more of the above-describedsecond therapeutic agents in the manufacture of a medicament, either asa single composition or as separate dosage forms, for treatment orprevention in a subject of a disease, disorder or symptom set forthabove. Another aspect of the invention is a compound of Formula I foruse in the treatment or prevention in a subject of a disease, disorderor symptom thereof delineated herein.

EXAMPLES Example 1 Synthesis of N-(Methylsulfonyl)Nicotinamide (Compound100)

N-(methylsulfonyl)nicotinamide (Compound 100)

Nicotinic acid (1.0 g, 8.12 mmol) was dissolved in tetrahydrofuran (16mL) and oxalyl chloride (0.780 mL, 8.94 mmol) was added dropwise.Immediate effervescence was observed followed by precipitation of awhite solid at the end of the addition. One drop of dimethylformamidewas added and the reaction was allowed to stir at ambient temperaturefor thirty minutes. In a separate flask a solution of methyl sulfonamide(2a, 0.772 g, 8.12 mmol), triethylamine (1.47 mL, 10.55 mmol) andtetrahydrofuran (16 mL) was prepared. This solution was added to thesolution of acyl chloride dropwise. The reaction was warmed at 40° C.for 72 h. The reaction was then cooled and concentrated to give anorange semisolid from which the product was triturated withdichloromethane. The resulting solid was recrystallized from methanoland dichloromethane. The desired product was obtained as a white powder(0.440 g, 27% yield). ¹H NMR (400 MHz, d₆-DMSO): δ 9.09 (br s, 1H), 8.84(br s, 1H), 8.36-8.32 (m, 1H), 7.64-7.60 (m, 1H), 3.41 (s, 3H). MS(M+H): 201.1.

Example 2 Synthesis of2,4,5,6-Tetradeutero-N-(methylsulfonyl)nicotinamide (Compound 103)

2,4,5,6-tetradeutero-N-(methylsulfonyl)nicotinamide (Compound 103)

2,4,5,6-tetradeutero-nicotinic acid (0.1 g, 0.787 mmol, CDN Isotopes, 98atom % D) was dissolved in dimethylformamide (3.15 mL) and carbonyldiimidazole (0.140 g, 0.865 mmol) was added in a single portion. Thereaction was heated at 40° C. for thirty minutes. Methyl sulfonamide 2a(0.082 g, 0.865 mmol) was added followed by1,8-diazabicyclo[5.4.0]undec-7-ene (0.129 mL, 0.865 mmol). The reactionwas stirred at ambient temperature until deemed complete by TLCanalysis. The reaction mixture was concentrated in vacuo and theresulting residue loaded onto a silica gel pre-column. Purification bysilica gel column chromatography on an ISCO system (0-100% ethylacetate/heptanes then 0-20% methanol/dichloromethane) afforded thedesired product 103 as an off-white solid (0.14 g, 0.583 mmol, 74%yield). NMR (400 MHz, CDCl₃): δ 3.48 (s, 3H). ²H NMR (400 MHz, CHCl₃): δ9.09 (br s, 1H), 8.84 (br s, 1H), 8.36-8.32 (m, 1H), 7.64-7.60 (m, 1H).MS (M+H): 205.1.

Notable in the ¹H-NMR spectrum above was the absence of peaks in thearomatic region at around 6-10 ppm indicating an absence of hydrogen atthe 2,4,5, and 6 positions of the nicotimamide ring.

Example 3 Evaluation of Metabolic Stability in Human Liver Microsomes

Microsomal Assay:

Human liver microsomes (20 mg/mL) are obtained from Xenotech, LLC(Lenexa, Kans.). β-nicotinamide adenine dinucleotide phosphate, reducedform (NADPH), magnesium chloride (MgCl₂), and dimethyl sulfoxide (DMSO)are purchased from Sigma-Aldrich.

Determination of Metabolic Stability:

7.5 mM stock solutions of test compounds are prepared in DMSO. The 7.5mM stock solutions are diluted to 12.5-50 μM in acetonitrile (ACN). The20 mg/mL human liver microsomes are diluted to 0.625 mg/mL in 0.1 Mpotassium phosphate buffer, pH 7.4, containing 3 mM MgCl₂. The dilutedmicrosomes are added to wells of a 96-well deep-well polypropylene platein triplicate. A 10 μL aliquot of the 12.5-50 μM test compound is addedto the microsomes and the mixture is pre-warmed for 10 minutes.Reactions are initiated by addition of pre-warmed NADPH solution. Thefinal reaction volume is 0.5 mL and contains 0.5 mg/mL human livermicrosomes, 0.25-1.0 μM test compound, and 2 mM NADPH in 0.1 M potassiumphosphate buffer, pH 7.4, and 3 mM MgCl₂. The reaction mixtures areincubated at 37° C., and 50 μL aliquots are removed at 0, 5, 10, 20, and30 minutes and added to shallow-well 96-well plates which contain 50 μL,of ice-cold ACN with internal standard to stop the reactions. The platesare stored at 4° C. for 20 minutes after which 100 μL of water is addedto the wells of the plate before centrifugation to pellet precipitatedproteins. Supernatants are transferred to another 96-well plate andanalyzed for amounts of parent remaining by LC-MS/MS using an AppliedBio-systems API 4000 mass spectrometer. The same procedure is followedfor the non-deuterated counterpart of the compound of Formula I and thepositive control, 7-ethoxycoumarin (1 μM). Testing is done intriplicate.

Data Analysis:

The in vitro t_(1/2)s for test compounds are calculated from the slopesof the linear regression of % parent remaining (ln) vs incubation timerelationship.in vitro t _(1/2)=0.693/kk=−[slope of linear regression of % parent remaining (ln) vs incubationtime]

Data Analysis is Performed Using Microsoft Excel Software.

Without further description, it is believed that one of ordinary skillin the art can, using the preceding description and the illustrativeexamples, make and utilize the compounds of the present invention andpractice the claimed methods. It should be understood that the foregoingdiscussion and examples merely present a detailed description of certainpreferred embodiments. It will be apparent to those of ordinary skill inthe art that various modifications and equivalents can be made withoutdeparting from the spirit and scope of the invention.

I claim:
 1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is selectedfrom C₁-C₆ alkyl, phenyl, a 5-10-membered heteroaryl, or a 3-10-memberedheterocycloalkyl, wherein R¹ comprises at least one deuterium atom; andn is 0 or an integer from 1 to
 4. 2. The compound of claim 1, wherein R¹is C₁-C₆ alkyl substituted with one or more deuterium atoms.
 3. Thecompound of claim 1 or claim 2, wherein n is
 0. 4. The compound of claim1, wherein the compound is selected from

or a pharmaceutically acceptable salt thereof.
 5. A compound representedby the following structural formula:

or a pharmaceutically acceptable salt thereof.
 6. A compound representedby the following structural formula:

or a pharmaceutically acceptable salt thereof.
 7. The compound of claim4, 5, or 6, wherein any atom not designated as deuterium is present atits natural isotopic abundance.
 8. A pyrogen-free pharmaceuticalcomposition comprising an effective amount of the compound of claim 4, 5or 6 or a pharmaceutically acceptable salt thereof; and apharmaceutically acceptable carrier.
 9. The composition of claim 8,additionally comprising a second therapeutic agent selected from asteroid; a cholesterol lowering agent; an anti-diabetic agent; ananti-platelet agent; a pain-reducing agent; a prostaglandin-D2antagonist; and a prostaglandin-D2 receptor antagonist.
 10. Thecomposition of claim 9, wherein the second therapeutic agent is selectedfrom lovastatin, simvastatin, rosuvastatin, atorvastatin, ezetimibe,aspirin, laropiprant, colestipol, cholestyramine, fenofibrate,rosiglitazone, pioglitazone, clopidogrel, prednisone, oxycodone,prednisone and apple pectin, and combinations of any of the foregoing.11. The composition of claim 8, comprising a second therapeutic agentselected from lovastatin, simvastatin and a combination of simvastatinand ezetimibe.